Submissions for variant NM_017882.3(CLN6):c.307C>T (p.Arg103Trp)

gnomAD frequency: 0.00001  dbSNP: rs201095412

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595470	SCV000703152	uncertain significance	not provided	2016-12-02	criteria provided, single submitter	clinical testing
Invitae	RCV001051368	SCV001215519	pathogenic	Neuronal ceroid lipofuscinosis	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 103 of the CLN6 protein (p.Arg103Trp). This variant is present in population databases (rs201095412, gnomAD 0.03%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis and/or spinocerebellar ataxia (PMID: 18846690, 27903347, 31743419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN6 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg103 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21549341, 30561534). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000678437	SCV002012075	likely pathogenic	Ceroid lipofuscinosis, neuronal, 6A	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000498240.4, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000426, PM2). A different missense change at the same codon (p.Arg103Gln) has been reported as pathogenic (PMID: 30561534, 27903347, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.926, 3Cnet: 0.941, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Translational Research Program on Neuronal Ceroid Lipofuscinosis, Center for the Study of Inborn Errors of Metabolism	RCV000678437	SCV000804303	pathogenic	Ceroid lipofuscinosis, neuronal, 6A		no assertion criteria provided	research	Late Infantile NCL / Kufs disease